The aim of this proposal is to develop a novel immunotherapeutic that will prevent and treat potentially life- threatening infection with influenza virus. The proposal is based on the fact that mannose-binding lectin (MBL) is a broad-spectrum molecule of innate immunity. This serum protein recognizes a wide range of pathogens including viruses. Preliminary data indicate that 1) recombinant human MBL (rhMBL) neutralizes influenza virus, and 2) There is increased susceptibility to virus infection in mice lacking MBL. These observations support MBL as a strong candidate as an immunotherapeutic agent to treat influenza virus infection. A key goal of this project is first to evaluate clinical grade rhMBL that has been used in Phase I clinical studies, and second generation derivatives incorporating a part of L-ficolin, another lectin-like serum protein, that may have increased activity and increased pharmacologic properties. Preliminary studies demonstrate that these novel chimeric lectins bind mannan, the same carbohydrate that is expressed on influenza viruses and activate the lectin complement pathway. This grant proposal will leverage the infrastructure of the Program of Developmental Immunology at Massachusetts General Hospital, the extensive scientific experience of the investigators in the field of innate immunity and lung inflammation, the specialized resources and extensive scientific knowledge of the investigators in the field of influenza virus infection at the Department of Medicine at Boston University School of Medicine and the Department of Paediatrics &Adolescent Medicine and Microbiology at The University of Hong Kong and The Department of Medicine at Beth Israel Deaconess Medical Center and the product development expertise of Enzon, a US biotechnology company that acquired rights to produce recombinant lectin chimeras. We will evaluate the efficacy of rhMBL and lectin chimeras to activate the lectin complement pathway and to modulate phagocytic functions in vitro. We will also investigate the therapeutic potential of these lectins in mice genetically deficient for the MBL, complement component 3, ficolin-A (equivalent to human L-ficolin) or combinations these materials to elucidate the relative roles of each innate immune molecule in influenza virus infection. The goal is to develop a formulation of rhMBL or a derivative that could be used as prophylactic and/or therapeutic agetns against influenza virus infection.